The purpose of this study was to evaluate the factors implicated in the pathogenesis of anemia of malignancy. To accomplish this end 240 normal or splenectomized rats with or without the solid form of Walker 256 Carcinosarcoma were studied. Extensive local cancer invasion of the shoulder region was accompanied by anemia (Hgb 8.7 plus or minus 0.3g/100ml), decreased Cr51 body red cell mass (1.7 plus or minus 0.1% body wt. vs. 2.2 plus or minus 0.1% in normals), and a modestly shortened Cr51 RBC survival (T/2 of 7.8 plus or minus 0.6 days vs. 9.9 plus or minus 0.7 days in normals). As a result of extensive splenic erythropoiesis in malignant rats, there was increased incorporation of transferrin-bound Fe59 into red cells (71 plus or minus 5% vs. 59 plus or minus 3% in normals. However, splenectomized rats with advanced cancer developed a greater degree of anemia (Hgb 7.2 plus or minus 0.5g/100 ml) associated with a significantly decreased incorporation of Fe59 into red cells (36 plus or minus 4% vs. 58 plus or minus 3% in control splenectomized rats). Hemoglobin reutilization studies using Fe59-labelled, heat-damaged rat erythrocytes revealed a normal to moderately decreased iron reutilizaton in anemic malignant rats. Marrow cell response to exogenous erythropoietin was determined by measuring Fe59 heme synthesis in marrow cell suspensions cultured for 24 hrs. with or without erythropoietin. Erythropoietin enhanced heme synthesis by less than 30% in malignant rat marrow cultures as compared to greater than 200% stimulation in normal marrow cultures. Plasma erythropoietin levels (measured in vitro) were appropriately increased for the degree of anemia in malignant rats. These experiments confirm the importance of decreased marrow responsiveness to erythropoietin resulting in decreased red cell production in the anemia of malignancy. BIBLIOGRAPHIC REFEFENCES: Zucker, S., Lysik, R.M., DiStefano, J.: Pathogenesis of Anemia of Malignancy. Clin Res 23:286A, 1975 (Abstract). Zarrabi, M.H., Lysik, R. M., Zucker, S.: Reutilization of Iron in the Anemia of Experimental Malignancy. Clin Res 23:583A, 1976 (Abstract).